'''Crystal Structure of E. coli Argininosuccinate Synthetase in complex with Aspartate and Citrulline'''
===Crystal Structure of E. coli Argininosuccinate Synthetase in complex with Aspartate and Citrulline===
==Overview==
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BACKGROUND: Argininosuccinate synthetase (AS) is the rate-limiting enzyme of both the urea and arginine-citrulline cycles. In mammals, deficiency of AS leads to citrullinemia, a debilitating and often fatal autosomal recessive urea cycle disorder, whereas its overexpression for sustained nitric oxide production via the arginine-citrulline cycle leads to the potentially fatal hypotension associated with septic and cytokine-induced circulatory shock. RESULTS: The crystal structure of E. coli AS (EAS) has been determined by the use of selenomethionine incorporation and MAD phasing. The structure has been refined at 1.6 A resolution in the absence of its substrates and at 2.0 A in the presence of aspartate and citrulline (EAS*CIT+ASP). Each monomer of this tetrameric protein has two structural domains: a nucleotide binding domain similar to that of the "N-type" ATP pyrophosphatase class of enzymes, and a novel catalytic/multimerization domain. The EAS*CIT+ASP structure clearly describes the binding of citrulline at the cleft between the two domains and of aspartate to a loop of the nucleotide binding domain, whereas homology modeling with the N-type ATP pyrophosphatases has provided the location of ATP binding. CONCLUSIONS: The first three-dimensional structures of AS are reported. The fold of the nucleotide binding domain confirms AS as the fourth structurally defined member of the N-type ATP pyrophosphatases. The structures identify catalytically important residues and suggest the requirement for a conformational change during the catalytic cycle. Sequence similarity between the bacterial and human enzymes has been used for providing insight into the structural and functional effects of observed clinical mutations.
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==About this Structure==
==About this Structure==
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[[Category: Lemke, C T.]]
[[Category: Lemke, C T.]]
[[Category: N-type atp pyrophosphatase]]
[[Category: N-type atp pyrophosphatase]]
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Revision as of 06:58, 2 July 2008
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The 1.6 A crystal structure of E. coli argininosuccinate synthetase suggests a conformational change during catalysis., Lemke CT, Howell PL, Structure. 2001 Dec;9(12):1153-64. PMID:11738042
